Optimal Leapfrogging

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An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression

TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53–PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors. Significance: We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy

A future for Hashima: pornography, representation and time

This article sets out to investigate the relationship between ruins, futurity, and ‘ruin porn’ - a visual mode of representation that all too often seeks to fix post-industrial ruins as mere aesthetic objects, devoid of history and/or temporality. It does so by focusing on performance, which, in this context, is understood as a processual mode of art-making that provides spectators with an experience of time. In this expanded definition of performance, as one may perhaps expect, the performativity of the object is not limited to the theatrical event alone; rather, it now inheres in sometimes uncanny durational aspects of both still and moving images. The essay proceeds in three stages. Part one provides a historical and theoretical overview of the type of performance inherent in ‘ruin porn’; part two critiques two images from Yves Marchand's and Romain Meffre's Gunkanjima (2013), a photo album that attempted to document the ruins of Hashima, an island situated 15 kilometres from Nagasaki City in the East China Sea; and part three investigates the very different aesthetic at work in Lee Hassall's film Return to Battleship Island (2013) which was made in response to AHRC- funded project, ‘The Future of Ruins: Reclaiming Abandonment and Toxicity on Hashima Island’ (2013). In this reading of Return to Battleship Island , the onus is on showing how Hassall's film, in its representation of Hashima's crumbling apartment blocks and industrial buildings, intentionally sought to contest the atemporal logic of ‘ruin porn’ by attempting to endow the viewing experience with a sense of futurity. Crucially, this does not mean that film represented the future as an object, but, on the contrary, tried to make it palpable, as something one undergoes physically in the very act of reception

Fast, Effective Dynamic Compilation

Dynamic compilation enables optimizations based on the values of invariant data computed at run-time. Using the values of these runtime constants, a dynamic compiler can eliminate their memory loads, perform constant propagation and folding, remove branches they determine, and fully unroll loops they bound. However, the performance benefits of the more efficient, dynamically-compiled code are offset by the run-time cost of the dynamic compile. Our approach to dynamic compilation strives for both fast dynamic compilation and high-quality dynamically-compiled code: the programmer annotates regions of the programs that should be compiled dynamically; a static, optimizing compiler automatically produces pre-optimized machine-code templates, using a pair of dataflow analyses that identify which variables will be constant at run-time; and a simple, dynamic compiler copies the templates, patching in the computed values of the run-time constants, to produce optimized, executable code. Our work..

The Theatre of Photography - Special Edition of Photography and Culture

This issue of Photography and Culture is edited by Joel Anderson and Weibke Leister and casts light on the various meeting points of the Theatre of Photography